Responses to DNA damage and regulation of cell cycle checkpoints by the ATM protein kinase family

The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress.

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The RIO kinases: An atypical protein kinase family required for ribosome biogenesis and cell cycle progression

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics ◽

10.1016/j.bbapap.2005.07.037 ◽

2005 ◽

Vol 1754 (1-2) ◽

pp. 14-24 ◽

Cited By ~ 72

Author(s):

Nicole LaRonde-LeBlanc ◽

Alexander Wlodawer

Keyword(s):

Cell Cycle ◽

Protein Kinase ◽

Ribosome Biogenesis ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Atypical Protein Kinase ◽

Protein Kinase Family ◽

Kinase Family

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Specific Role of Chk1 Phosphorylations in Cell Survival and Checkpoint Activation

Molecular and Cellular Biology ◽

10.1128/mcb.01611-06 ◽

2007 ◽

Vol 27 (7) ◽

pp. 2572-2581 ◽

Cited By ~ 111

Author(s):

Hiroyuki Niida ◽

Yuko Katsuno ◽

Birendranath Banerjee ◽

M. Prakash Hande ◽

Makoto Nakanishi

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Protein Kinase ◽

Cell Survival ◽

Cell Cycle Checkpoints ◽

Mitotic Catastrophe ◽

Wild Type ◽

Checkpoint Activation ◽

Multifunctional Protein

ABSTRACT Chk1 is a multifunctional protein kinase that plays essential roles in cell survival and cell cycle checkpoints. Chk1 is phosphorylated at multiple sites by several protein kinases, but the precise effects of these phosphorylations are largely unknown. Using a knockout-knockin system, we examined the abilities of Chk1 mutants to reverse the defects of Chk1-null cells. Wild-type Chk1 could rescue all the defects of Chk1-null cells. Like endogenous Chk1, wild-type Chk1 localized in both the cytoplasm and the nucleus, and its centrosomal association was enhanced by DNA damage. The mutation at S345 resulted in mitotic catastrophe, impaired checkpoints, and loss of the ability to localize in the cytoplasm, but the mutant retained the ability to be released from chromatin upon encountering genotoxic stressors. In contrast, the mutation at S317 resulted in impaired checkpoints and loss of chromatin release upon encountering genotoxic stressors, but its mutant retained the abilities to prevent mitotic catastrophes and to localize in the cytoplasm, suggesting the distinct effects of these phosphorylations. The forced immobilization of S317A/S345A in centrosomes resulted in the prevention of apoptosis in the presence or absence of DNA damage. Thus, two-step phosphorylation of Chk1 at S317 and S345 appeared to be required for proper localization of Chk1 to centrosomes.

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Faculty Opinions recommendation of Characterization of DNA damage-dependent cell cycle checkpoints in a menin-deficient model.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1163041.623690 ◽

2009 ◽

Author(s):

Patrick Gaudray

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Checkpoints ◽

Dependent Cell

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Involvement of 53BP1, a p43 Binding Protein, in Chk2 Phosphorylation of p53 and DNA Damage Cell Cycle Checkpoints

10.21236/ada417278 ◽

2003 ◽

Author(s):

Bin Wang ◽

Stephen J. Elledge

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Binding Protein ◽

Cell Cycle Checkpoints ◽

Damage Cell

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Differential Roles of ATM- and Chk2-Mediated Phosphorylations of Hdmx in Response to DNA Damage

Molecular and Cellular Biology ◽

10.1128/mcb.00562-06 ◽

2006 ◽

Vol 26 (18) ◽

pp. 6819-6831 ◽

Cited By ~ 51

Author(s):

Yaron Pereg ◽

Suzanne Lam ◽

Amina Teunisse ◽

Sharon Biton ◽

Erik Meulmeester ◽

...

Keyword(s):

Dna Damage ◽

Protein Kinase ◽

Posttranslational Modifications ◽

Genomic Stability ◽

Double Strand Breaks ◽

Nuclear Accumulation ◽

Strand Breaks ◽

Damage Response ◽

Subsequent Degradation ◽

Atm Protein

ABSTRACT The p53 tumor suppressor plays a major role in maintaining genomic stability. Its activation and stabilization in response to double strand breaks (DSBs) in DNA are regulated primarily by the ATM protein kinase. ATM mediates several posttranslational modifications on p53 itself, as well as phosphorylation of p53's essential inhibitors, Hdm2 and Hdmx. Recently we showed that ATM- and Hdm2-dependent ubiquitination and subsequent degradation of Hdmx following DSB induction are mediated by phosphorylation of Hdmx on S403, S367, and S342, with S403 being targeted directly by ATM. Here we show that S367 phosphorylation is mediated by the Chk2 protein kinase, a downstream kinase of ATM. This phosphorylation, which is important for subsequent Hdmx ubiquitination and degradation, creates a binding site for 14-3-3 proteins which controls nuclear accumulation of Hdmx following DSBs. Phosphorylation of S342 also contributed to optimal 14-3-3 interaction and nuclear accumulation of Hdmx, but phosphorylation of S403 did not. Our data indicate that binding of a 14-3-3 dimer and subsequent nuclear accumulation are essential steps toward degradation of p53's inhibitor, Hdmx, in response to DNA damage. These results demonstrate a sophisticated control by ATM of a target protein, Hdmx, which itself is one of several ATM targets in the ATM-p53 axis of the DNA damage response.

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Molecular Physiology of SPAK and OSR1: Two Ste20-Related Protein Kinases Regulating Ion Transport

Physiological Reviews ◽

10.1152/physrev.00009.2012 ◽

2012 ◽

Vol 92 (4) ◽

pp. 1577-1617 ◽

Cited By ~ 71

Author(s):

Kenneth B. Gagnon ◽

Eric Delpire

Keyword(s):

Protein Kinase ◽

Multiple Organ ◽

Genetically Engineered ◽

Related Protein ◽

Molecular Physiology ◽

Cancer Proliferation ◽

Protein Kinase Family ◽

Kinase Family ◽

Organ Systems ◽

And Migration

SPAK (Ste20-related proline alanine rich kinase) and OSR1 (oxidative stress responsive kinase) are members of the germinal center kinase VI subfamily of the mammalian Ste20 (Sterile20)-related protein kinase family. Although there are 30 enzymes in this protein kinase family, their conservation across the fungi, plant, and animal kingdom confirms their evolutionary importance. Already, a large volume of work has accumulated on the tissue distribution, binding partners, signaling cascades, and physiological roles of mammalian SPAK and OSR1 in multiple organ systems. After reviewing this basic information, we will examine newer studies that demonstrate the pathophysiological consequences to SPAK and/or OSR1 disruption, discuss the development and analysis of genetically engineered mouse models, and address the possible role these serine/threonine kinases might have in cancer proliferation and migration.

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